Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
  • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
  • A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
  • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
  • A61L24/043—Mixtures of macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
  • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
  • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F116/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical
  • C08F116/02—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by an alcohol radical
  • C08F116/04—Acyclic compounds
  • C08F116/06—Polyvinyl alcohol ; Vinyl alcohol
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F16/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical
  • C08F16/02—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by an alcohol radical
  • C08F16/04—Acyclic compounds
  • C08F16/06—Polyvinyl alcohol ; Vinyl alcohol
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F8/00—Chemical modification by after-treatment
  • C08F8/18—Introducing halogen atoms or halogen-containing groups
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
  • C09D129/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal, or ketal radical; Coating compositions based on hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Coating compositions based on derivatives of such polymers
  • C09D129/02—Homopolymers or copolymers of unsaturated alcohols
  • C09D129/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2400/00—Materials characterised by their function or physical properties
  • A61L2400/06—Flowable or injectable implant compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

• the present invention relates to radiopaque, non-biodegradable, water-insoluble iodinated polymers, and more particularly to radiopaque, non-biodegradable, water-insoluble, iodinated benzyl ethers of polyvinyl alcohol), to their use as embolizing agents, to a process for producing thereof, to injectable embolizing compositions containing thereof and the uses thereof, to coating compositions containing thereof and to micro- and nanoparticles made thereof.
• the embolization of a blood vessel is important in preventing/controlling bleeding (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm) or to ablate diseased tissue (e.g., tumors, etc.) by cutting off its blood supply.
• bleeding e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm
• ablate diseased tissue e.g., tumors, etc.
• Endovascular embolization of blood vessels is known to be conducted as alternative to surgical interventions for a variety of purposes including the endovascular treatment of tumors, the treatment of lesions such as aneurysms, arteriovenous malformations, arteriovenous fistula, uncontrolled bleeding and the like.
• Endovascular embolization of blood vessels is accomplished via catheter techniques which permit the selective placement of the catheter at the vascular site to be embolized.
• embolizing compositions in the treatment of aneurysms or
• arteriovenous malformations is advantageous since the polymeric materials fill the inside of the aneurysms or AVM and solidify in the shape of the aneurysm or AVM, therefore the aneurysm or AVM will be completely excluded from the blood circulation.
• injectable embolizing compositions containing polymeric materials as embolizing agents may be used for treating tumors by direct puncture. In such a case, the embolizing composition is directly injected into the tumoral tissue or the vascular bed surrounding the tumor via a needle technology.
• Known polymeric materials employed in embolizing compositions include for example those wherein a preformed polymer in situ precipitates from a carrier solution at the vascular site or into the tumor.
• the preformed polymer In embolizing compositions, the preformed polymer must be selected to be capable of rapid precipitation to form a well defined cohesive solid or semi-solid mass, space-filling material upon contact with blood or any other body aqueous environment in a tissue.
• compositions should be sterile, stable, biocompatible, and further highly radiopaque to allow for an efficient imaging using current radiology techniques. This last property is necessary in order to visualize the embolizing composition during injection, deposition into the vascular site, and clinical follow-up.
• a number of documents disclose liquid formulations intended for the embolization of blood vessels and containing a water-insoluble, organo-soiuble biocompatible preformed polymer dissolved in a biocompatible water-miscible organic solvent, and a solid water-insoluble biocompatible radiopaque contrast agent such as tantalum, tantalum oxide, tungsten, bismuth trioxide and barium sulfate.
• radiopaque embolizing compositions precipitating upon contact with blood, are simple physical mixtures of a preformed polymer dissolved in a water-miscible organic solvent and a conventional radiopaque contrast agent.
• US-A-5,580,568 discloses compositions suitable for use in embolizing blood vessels which comprise a cellulose diacetate polymer, a biocompatible solvent such as DMSO and a water insoluble contrast agent such as tantalum, tantalum oxide and barium sulfate.
• US-A-5,851 ,508 discloses compositions suitable for use in embolizing blood vessels which comprises an ethylene vinyl alcohol copolymer, a biocompatible solvent such as DMSO and a water insoluble contrast agent such as tantalum, tantalum oxide and barium sulfate.
• compositions for use in embolizing blood vessels which comprise a biocompatible polymer selected from cellulose acetates, cellulose acetate propionates, cellulose acetate butyrates, ethylene vinyl alcohol
• copolymers hydrogels, polyacrylonitrile, polyvinylacetate, nitrocellulose, copolymers of urethane/carbonate, copolymers of styrene/maleic acid and mixtures thereof, a biocompatible solvent such as DMSO, ethanol and acetone, and a contrast agent such as tantalum, tantalum oxide, tungsten and barium sulfate.
• a biocompatible solvent such as DMSO, ethanol and acetone
• a contrast agent such as tantalum, tantalum oxide, tungsten and barium sulfate.
• the radiopaque contrast agent is suspended in the polymer solution, so that these embolizing compositions are heterogeneous dispersions.
• ONYXTM a mixture of ethylene-vinyl alcohol copolymer (EVOH) dissolved in DMSO, with micronized tantalum powder in the liquid polymer/DMSO mixture to provide fluoroscopic visualization.
• EVOH ethylene-vinyl alcohol copolymer
• ONYXTM is delivered through a microcatheter to the target lesion under
• DMSO dimethyl methacrylate
• ONYXTM is available in a range of liquid viscosities intended to have delivery and precipitation characteristics optimized for the type of lesion being treated.
• these formulations have the following drawbacks.
• radiopaque contrast agent is suspended in the polymer solution, homogeneous radiopacity may not be ensured with respect to possible
• the radiopaque contrast agent also limits non-invasive follow-up imaging by CT scanning because of beam-hardening artifacts. Furthermore, the entrapment of the metallic radiopaque contrast agent is not ensured so that phase separation may occur.
• the radiopaque contrast agent does not reflect the position of the polymer and implant visibility may change during radiological imaging follow-up studies. Released metallic radiopaque contrast agents are potentially toxic.
• l-PVA iodinated polyvinyl alcohol
• Polyvinyl Alcohol Polymer A New, Nonadhesive, Iodine-Containing Liquid Embolic Agenf ; O. Dudeck, O. Jordan et al., Am. J. Neuroradiol., 27:1900-1906, 2006, "Organic solvents as vehicles for precipitating liquid embolics"; O. Dudeck, O.
• this l-PVA lacks stability with respect to hydrolysis, and when used as embolizing agent, undergoes partial degradation leading to potentially toxic degradation products in the body over time.
• the present inventors have focused their research on the need to provide a new iodinated polyvinyl alcohol) which has an improved stability, and have surprisingly found a new iodinated polyvinyl alcohol) which has not only an improved stability with respect to hydrolysis, but which is also expected to provide liquid embolizing compositions having higher concentration of embolizing agent, and therefore lower volume of organic solvent due to its unexpected low viscosity in solution, and have thus achieved the present invention.
• the present invention provides a radiopaque, non- biodegradable, water-insoluble iodinated benzyl ether of polyvinyl alcohol)
• iodo-benzylether-PVA consisting of a polyvinyl alcohol
• the present invention provides a process for preparing the iodo-benzylether-PVA of the present invention, said process comprising reacting a 0 - 100 % hydroiyzed polyvinyl alcohol) as a starting PVA with a iodinated benzyl derivative comprising 1 - 4 iodine atoms per benzyl group in a polar aprotic solvent in the presence of a base in anhydrous conditions.
• the present invention provides a use of the
• the present invention provides an injectable embolizing composition comprising the iodo-benzylether-PVA of the present invention and a water-miscible, biocompatible solvent solubilizing the iodo- benzylether-PVA, wherein the concentration of the iodo-benzylether-PVA in the composition is selected in the range of 5 - 65 w/w % so that the composition is capable of forming a cohesive mass upon contact with a body fluid by precipitation of the iodo-benzylether-PVA.
• the present invention provides a use of the injectable embolizing composition of the present invention for forming in-situ a cohesive mass in a blood vessel such as arteriovenous malformation (AVMs) or vascular aneurysms.
• AVMs arteriovenous malformation
• vascular aneurysms vascular aneurysms
• the present invention provides a use of the injectable embolizing composition of the present invention for forming in-situ a cohesive mass into a tumor.
• the present invention provides a use of the injectable embolizing composition of the present invention for forming in-situ a semi-solid implant into a tumor for treating the tumor by hyperthermia.
• the present invention provides a use of the injectable embolizing composition of the present invention for forming in-situ a semi-solid implant for treating urinary incontinence.
• the present invention provides a coating composition for forming a coating on a medical device comprising the iodo-benzylether-PVA of the present invention and a solvent solubilizing the iodo-benzylether-PVA, wherein the concentration of the iodo-benzylether-PVA in the composition is selected in the range of 5 - 65 w/w % so that the composition is capable of forming a radiopaque coating after application on a medical device and solvent evaporation.
• the present invention provides particles, selected from microparticles and nanoparticles, formed of the iodo-benzylether-PVA of the present invention.
• Fig. 1 shows the 1 H-NMR spectrum of 2,3,5-triiodobenzylether of polyvinyl alcohol) of the present invention prepared according to Example 1.
• Fig. 2 shows the H-NMR spectrum of 4-iodobenzylether of polyvinyl alcohol) of the present invention prepared according to Example 2.
• Fig. 3a is a photograph showing precipitation in water of 2,3,5-triiodobenzylether of polyvinyl alcohol) prepared according to Example 1 dissolved at a concentration of 10 % w/w in N-methylpyrrolidone (NMP).
• NMP N-methylpyrrolidone
• Fig. 3b is a photograph showing precipitation in water of 2,3,5-triiodobenzylether of polyvinyl alcohol) prepared from PVA 13kDa according to Example 1 , dissolved at a concentration of 33 % w/w in NMP.
• Fig. 4 is a photograph showing precipitation in water of 4-iodobenzylether of polyvinyl alcohol) prepared from PVA 13kDa according to Example 2, dissolved at a concentration of 33 % w/w in DMSO.
• Fig. 5 represents a graph showing the change of viscosity [mPa.s] of two solutions containing a iodo-benzylether-PVA of the present invention prepared from PVA 13kDa in relation to a change of the concentration (% w/w) of the iodo- benzylether-PVA in solution.
• Fig. 6 represents a graph illustrating the radiopacity of two injectable embolizing compositions of the present invention, as compared with the radiopacity of OnyxTM 18 and OnyxTM 34.
• Fig. 7a is a photograph showing embolization of an aneurysm mode! with an injectable embolizing composition of the present invention containing 33 % w/w of 2,3,5-triiodobenzylether of polyvinyl alcohol) dissolved in NMP.
• Fig. 7b is a photograph showing embolization of an aneurysm model with an injectable embolizing composition of the present invention containing 33 % w/w of 4-iodobenzylether of polyvinyl alcohol) dissolved in NMP.
• Fig. 7c is a photograph showing embolization of an aneurysm model with
• FIG. 8 shows the 1 H-NMR spectrum of MTIB-PVA 47kDa of the present invention prepared according to Example 13.
• Figs. 9a et 9b are photographic (Fig. 9a) and fluoroscopic x-ray (Fig. 9b) images of plugs obstructing hydrogel model obtained from an injectable embolizing
• Fig. 11 b is a photograph showing a hyperthermic semi-solid smooth implant formed after injection of the viscous injectable embolizing formulation of the present invention shown in Fig. 11a into hydrogel model, as reported in Example 16.
• Fig. 12 represents a graph illustrating the temperature increase obtained with the hyperthermic implant shown in Fig. 11 b under exposure to an alternating magnetic field.
• Fig. 14 represents a catheter coated with a coating composition of the present invention as reported in Example 18.
• Fig. 15 represents a graph illustrating the evolution of the absorbance of nanoparticle degradation products for the 4-mono-iodobenzylether-PVA 47kDa and 4-mono-iodobenzoate-PVA 47kDa as reported in Example 20.1.
• Fig. 16 represents a graph illustrating the evolution of the absorbance of nanoparticle degradation products for the 2,3,5-tri-iodobenzylether-PVA 13kDa and 2,3,5-tri-iodobenzoate-PVA 13 kDa as reported in Example 20.2.
• iodo-benzylether-PVA of the present invention is a radiopaque, nonbiodegradable, water-insoluble iodinated benzyl ether of polyvinyl alcohol) consisting of a polyvinyl alcohol) having covalently grafted thereon iodinated benzyl groups comprising 1 - 4 iodine atoms per benzyl group via ether linkages.
• the degree of substitution (DS) of the iodo-benzylether-PVA of the present invention is not particularly limited.
• the degree of substitution (DS) is preferably of at least 0.2.
• the degree of substitution is of at least 0.4, and more preferably of at least 0.5.
• the degree of substitution (DS) is defined as
• x represents the number of grafted repeating units
• x + y represents the total number of repeating units (grafted repeating units and non-grafted repeating units), as calcuiated from the integration of the NMR lines of the iodo-benzylether-PVA of the present invention.
• a grafted repeating unit may be represented by
• n represents the number of iodine atoms on benzyl group
• non-grafted repeating unit may be represented by CH 2 -CH—
• the iodine content (% I) of the iodo-benzylether-PVA of the present invention is not particularly limited, but should preferably be of at least 20 % (w/w) for making it sufficiently radiopaque.
• the iodo-benzy!ether-PVA has a iodine content of at least 40 % (w/w).
• the iodo-benzylether-PVA of the present invention may be either a iodo- benzylether-PVA wherein all the grafted iodinated benzyl groups are identical, or may be a iodo-benzylether-PVA, wherein the grafted iodinated benzyl groups are two or more different iodinated benzyl groups having different number of iodine atoms.
• the iodine content (% 1) of the iodo-benzylether-PVA of the present invention may be calculated from the degree of substitution (DS) as follows : DS X M (iodine) x n
• M (iodine) represents the atomic mass of iodine atom (i.e. ⁇ 127)
• n represents the number of iodine atoms per benzyl group (i.e. from 1 to 4)
• M (non-grafted) represents the molar mass of a non-grafted repeating unit
• (grafted) represents the molar mass of a grafted repeating unit (for example
• ⁇ 260 when the benzyl group has only one iodine as substituent ⁇ 386 when the benzyl group has only two iodine atoms as substituents, - 512 when the benzyl group has only three iodine atoms as substituents, and - 638 when the benzyl group has only four iodine atoms as substituents).
• the iodine content (% I) of the iodo-benzylether-PVA of the present invention is the sum of the contributions of each type of grafted iodinated benzyl groups.
• the iodine content (% I) of a iodo-benzylether-PVA grafted with two or more different iodinated benzyl groups having different number of iodine atoms may be calculated by determining the degree of substitution (DS) for each type of iodinated benzyl groups, then by calculating the iodine content (% I) based on said DS using the above formula for each type of iodinated benzyl groups, and finally by adding the iodine contents (% I) calculated for each type of iodinated benzyl groups.
• the iodine content may also be determined or confirmed by elemental analysis.
• the iodinated benzyl groups grafted on the polyvinyl alcohol must comprise 1 - 4 iodine atoms per benzyl group.
• the benzyl group may further comprise other substituents such as amino, amide, ester and/or carbamoyl groups in addition to iodine atom(s), but in a particularly preferred embodiment of the present invention, the benzyl group comprises only iodine atom(s) as
• each benzyl group comprises only one iodine atom as substituent, and more preferably one iodine atom on the C4-position of the benzyl group.
• each benzyl group comprises only three iodine atoms as substituents, and more preferably three iodine atoms on the C-2, C-3 and C-5 positions of the benzyl group.
• each benzyl group may comprise from 1 to 4 iodine atoms, in any positions on the benzyl group.
• the iodo-benzylether-PVA of the present invention have grafted thereon both iodinated benzyl groups comprising one iodine atom on the C4-position and iodinated benzyl groups comprising three iodine atoms on the C-2, C-3 and C-5 positions.
• the iodo-benzylether-PVA of the present invention may have grafted thereon other types and combinations of iodinated benzyl groups, provided that said iodinated benzyl groups comprises 1 - 4 iodine atoms per benzyl group.
• the average molar mass (M) of iodo-benzylether-PVA of the present invention is not particularly limited, and has to be determined depending on the chosen application.
• Molar mass of the iodo-benzylether-PVA of the present invention may be easily controlled by appropriately selecting the molar mass (M) of the starting PVA polymer to be grafted in the process for preparing the iodo-benzylether-PVA of the present invention.
• a iodo-benzylether-PVA having a too high molar mass would not be appropriate for use as embolizing agent in an embolization composition because it would lead to an embolization composition too viscous for being injected via a catheter, and a iodo-benzylether-PVA having a too low molar mass would be not appropriate for use as embolizing agent in a liquid embolizing composition because the iodo-benzylether-PVA would not precipitate as a cohesive mass forming a solid or semi-solid embolic implant.
• a iodo-benzylether-PVA having a high molar mass and therefore providing a high viscosity in solution is not preferable when used as embolizing agent in an embolizing composition because the embolizing
• composition should have a low concentration of embolizing agents in a high volume of solvent, which is not advantageous.
• the average molar mass (M) of the iodo-benzylether-PVA of the present invention depends on the molar mass of the starting PVA polymer used to prepare the iodo- benzylether-PVA of the present invention and on the degree of substitution of the iodo-benzylether-PVA of the present invention.
• the iodo-benzylether-PVA of the present invention may be prepared by an etherification reaction of PVA with a iodinated benzyl derivative.
• the iodo-benzylether-PVA of the present invention may be prepared by a process comprising reacting a 0 - 100 % hydrolyzed polyvinyl alcohol) (starting PVA) with a iodinated benzyl derivative comprising 1 - 4 iodine atoms per benzyl group in a polar aprotic solvent in the presence of a base in anhydrous conditions.
• Polyvinyl alcohol (PVA) is a polymeric chain made of carbon atoms with pendant hydroxy! groups, which may also contain some pendant acetyl groups.
• a 0 % hydrolyzed polyvinyl alcohol means a PVA containing 0 % of pendant hydroxyl groups and 100 % of pendant acetyl groups on the polymeric chain.
• a 100 % hydrolyzed polyvinyl alcohol means a PVA containing only pendant hydroxyl groups.
• the process for preparing the iodo-benzylether-PVA of the present invention comprises reacting a 75 - 100 % hydrolyzed poiy(vinyl alcohol) as the starting PVA with the iodinated benzyl derivative.
• the average molar mass (M) of the starting PVA used in the process of the present invention is not particularly limited, and has to be determined depending on the average molar mass (M) expected for the final iodo-benzylether-PVA, depending on the chosen application.
• composition is preferably not smaller than 5 ⁇ 00 Daltons and not greater than
• 200 ⁇ 00 Daltons more preferably in the range from 10 ⁇ 00 to 130 ⁇ 00 Daltons, and still more preferably in the range from 10 ⁇ 00 to 50 ⁇ 00 Daltons.
• commercial PVA which may be used as starting PVA in the process of the present invention may be a PVA of pharmaceutical grade obtained from Sigma-A!drich® Co. having a weight-average molar mass (Mw) of 13 ⁇ 00-23 ⁇ 00 Daltons and a degree of hydrolysis of 87 - 89 %.
• any commercial PVA having any degree of hydrolysis may be used for preparing the iodo-benzylether-PVA of the present invention according to the process of the present invention.
• the iodinated benzyl derivative is selected as a reagent to be grafted depending on the iodo-benzylether-PVA to be obtained, and may be for example a iodinated benzyl chloride, a iodinated benzyl bromide or a iodinated benzyl mesylate.
• a iodo-benzylether-PVA comprising one iodine atom on the C4-position of all the benzyl groups may prepared by using commercial 4- iodobenzyl bromide (for example obtained from Sigma-Aldrich® Co.) as iodinated benzyl derivative.
• a iodo-benzylether-PVA comprising three iodine atoms on the C-2, C-3 and C-5 positions on all the benzyl groups may be prepared by using 2,3,5-triiodobenzyl bromide as iodinated benzyl derivative. 2,3,5-Triiodobenzyl derivatives may be easily prepared as reported in the experimental part in Preparation Examples 1-4.
• benzyl groups including one iodine atom on the C4-position and benzyl groups including three iodine atoms on the C-2, C-3 and C-5 positions may be prepared by using a mixture of 4-iodobenzyl bromide and 2,3,5-triiodobenzyl bromide as iodinated benzyl derivative.
• a iodo-benzylether-PVA of the present invention having grafted thereon different benzyl groups may be prepared by using any mixture of two or more different iodinated benzyl derivatives comprising 1 - 4 iodine atoms per benzyl group.
• iodinated benzyl derivatives which may be used in the process of the present invention are either commercially available or may be easily prepared by the skilled person, for example from the corresponding iodinated benzoic acid or the corresponding iodinated benzyl alcohol according to conventional methods or according to methods based on those reported in the experimental part in
• Examples of the polar aprotic solvent for use in the synthesis process of the present invention may include DMSO (dimethylsulfoxide), NMP (N-methyl- pyrrolidone) and THF (tetrahydrofuran).
• Examples of the base for use in the process of the present invention may include NaOH, KOH and NaH,
• the polar aprotic solvent is NMP and the base is NaOH.
• the iodo-benzylether-PVA of the present invention obtained by this process may be further purified by conventional techniques including, but not limited to, precipitation/solubilization/precipitation cycles to reach the degree of purity required.
• the iodo-benzylether-PVA of the present invention is useful as embolizing agent in an injectable embolizing composition.
• the injectable embolizing composition of the present invention comprises the iodo- benzylether-PVA of the present invention and a water-miscible, biocompatible solvent solubilizing the iodo-benzylether-PVA of the present invention.
• the embolizing composition appropriately select the molar mass of the iodo-benzylether-PVA contained in the embolizing composition in order that it is not too high and not too low for this application.
• a preferable iodo-benzylether-PVA for use as embolic agent in an embolizing composition may be obtained by using, as starting PVA, a PVA having a molar mass not smaller than 5 ⁇ 00 Daitons and not greater than 200 ⁇ 00 Daitons, preferably in the range from 10 ⁇ 00 to 130 ⁇ 00 Daitons, and more preferably in the range from 10 ⁇ 00 to 50 ⁇ 00 Daitons.
• the concentration of a polymer in solution also affects not only the viscosity of the polymer solution but also the precipitation behaviour of the polymer.
• the concentration of the iodo-benzylether-PVA of the present invention in the embolizing composition is selected in the range of 5 - 65 w/w %, said selection being dependent on the targeted viscosity of the embolizing composition, which itself depends on the average moiar mass of the iodo-benzylether-PVA of the present invention used in the embolizing composition.
• said selection of the concentration of the iodo-benzylether-PVA of the present invention must lead to an embolizing composition which is injectable, i.e. which is not too viscous for being injected, and further which is capable of forming a cohesive solid or semi-solid mass upon contact with an aqueous media such as a body fluid by precipitation of the iodo- benzylether-PVA.
• the concentration of the iodo-benzylether-PVA of the present invention is selected to be as high as possible in order to provide an embolizing composition having a reduced quantity of solvent.
• the concentration of the iodo-benzylether-PVA of the present invention in the embolizing composition is selected in the range of 20 - 50 w/w %.
• the iodo-benzylether-PVA of the present invention used in the injectable embolizing composition of the present invention has a iodine content (% I) of at least 20 % (w/w), and more preferably of at least 40 % (w/w) in order to provide an improved radiopacity to the embolizing composition and also to the embolic mass formed by precipitation of the iodinated-benzylether-PVA upon contact of the embolizing composition with a body fluid.
• the water-miscible, biocompatible solvent used in the injectable embolizing composition of the present invention is not particularly limited, provided that it solubilizes the iodo-benzylether-PVA to form a homogeneous solution.
• the water-miscible, biocompatible solvent is selected from dimethyisuifoxide, N-methyipyrrolidone, giycofurol, pyrrolidone, ethanol, propylene glycol, polyethylene glycol, solketalTM, glycerol formal, tetrahydrofurfuryl alcohol, dimethyl isosorbide, ethyl lactate, hydroxyethyllactamide and N,N- dimethylacetamide, and more preferably from dimethyisufoxide (DMSO), N- methylpyrrolidone (NMP) and giycofurol.
• DMSO dimethyisufoxide
• NMP N- methylpyrrolidone
• the injectable embolizing composition of the present invention comprises one iodo-benzylether-PVA of the present invention.
• the iodo-benzylether-PVA of the present invention contained in the injectable embolizing composition of the present invention is a iodo-benzylether-PVA, wherein each benzyl group comprises one iodine atom on C-4 position (called “4-mono-iodobenzylether-PVA” or “MiB-PVA” below).
• the iodo-benzylether-PVA of the present invention contained in the injectable embolizing composition of the present invention is a iodo-benzylether-PVA wherein each benzyl group comprises 3 iodine atoms on C-2, C-3 and C-5 positions (called “2,3,5-tri-iodo-benzyelther-PVA” or “TIB-PVA” below).
• the injectable composition of the present invention may comprise two or more different iodo- benzylether-PVAs of the present invention having different number or different position of iodine atoms, provided that the total concentration of the iodo- benzylether-PVAs of the present invention contained in the injectable embolizing composition is selected in the range of 5 - 65 w/w %.
• the injectable embolizing composition of the present invention contains 4-mono-iodobenzylether PVA (MIB-PVA) and 2,3,5-tri- iodobenzylther-PVA (TIB-PVA) in variable proportions.
• iodo-benzylether-PVA based on, for instance, 4-monoiodo-benzylether-PVA (MIB-PVA) or 2, 3,5-tri iodo-benzylether- PVA (TIB-PVA) are quite different.
• 4-Monoiodo-benzylether-PVA MIB-PVA
• MIB-PVA is a softer material than 2,3,5-triiodo- benzylether-PVA (TIB-PVA), it is less fragile and brittle due to its lower glass transition temperature (Tg of MIB-PVA : 55 0 C, TIB-PVA : 111 °C).
• mixtures of MIB-PVA and TIB-PVA in variable proportions can be used to adjust the mechanical properties of the final precipitated implant.
• MIB-PVA and TIB-PVA dissolved in NMP show formulation viscosity, precipitation time and mechanical properties intermediate between that of MIB-PVA and TIB-PVA.
• Blend of MIB-PVA : TIB-PVA can therefore generate a family of liquid embolizing compositions, as illustrated in the Example 14.
• Tailoring implant properties can also be obtained using PVA polymers based on two or more kind of iodinated repeating units.
• PVA polymer grafted with MIB and TIB can be obtained by mixing in the reaction vial equal molar quantities of mono- iodobenzyl derivative and tri-iodobenzyl derivative.
• the resulting copolymer MTIB- PVA shows a close to 50 : 50 molar ratio of 4-mono-iodobenzy!ether and 2, 3, 5-th- iodobenzylether grafted groups, corresponding to a 38 : 62 MIB : TIB mass ratio.
• composition containing the selected concentration of the iodo-benzylether-PVA of the present invention and the selected water-miscible, biocompatible solvent is appropriate for use as an embolizing composition by carrying out a precipitation test of the composition in water.
• the injectable embolizing composition of the present invention is particularly useful when used for forming in-situ a cohesive solid or semi-solid mass in a blood vessel or into a tumor for treating human or other mammalian subjects.
• the embolizing composition of the present invention When used for embolizing blood vessels, in particular for treating lesions such as aneurysms, arteriovenous malformations, arteriovenous fistula, and tumors, it is introduced into the blood vessel via a catheter delivery means under fluoroscopy so that after precipitation of the iodo-benzylether-PVA, the blood vessel is embolized by the embolic mass formed by the precipitated iodo-benzylether-PVA.
• the embolizing composition of the present invention When the embolizing composition of the present invention is used in the treatment of tumors by direct puncture, it is directly injected into the tumoral tissue via a needle technology so that after precipitation of the iodo-benzylether-PVA, tumor is filled with the embolic mass formed by the precipitated iodo-benzylether-PVA.
• the particular amount of the embolizing composition employed is dictated by the total volume of the vasculature or tissue to be embolized, the concentration of the iodo-benzylether-PVA, the rate of precipitation of the iodo-benzylether-PVA, etc.; the determination of such factors lies well within the competence of a person skilled in the art.
• the injectable embolizing composition of the present invention comprises drugs or biopharmaceuticals.
• the injectable embolizing composition including drugs or biopharmaceuticals is particularly useful for forming in-situ a cohesive solid or semi-solid mass loaded with said drugs or biopharmaceuticals and able to subsequently deliver in-situ by release the drugs or biopharmaceuticals.
• Example 17 illustrates the release of an anticancer agent, doxorubicine
• the injectable embolizing composition comprises superparamagnetic iron oxide nanoparticles (SPIONs).
• the injectable embolizing composition including SP!ONs is particularly useful for forming in-situ a solid or semi-solid implant loaded with said SPIONs into a tumor for treating the tumor by hyperthermia.
• SPIONs which are used in the injectable embolizing composition of the present invention may be adequately coated or encapsulated, or may be immobilized in silica beads.
• SPIONs which may be included in the injectable embolization composition of the present invention may be commercially available SPIONs, for example SPIONs immobilized in silica beads such as MagSiiica 50-85 (Evonik, Germany), or may be for example SPIONS as disclosed in WO-A-2006/125452 or by Matthieu
• Example 16 illustrates the in-situ formation of an hyperthermic implant by using the injectable embolizing composition of the present invention loaded with SPIONs immobilized in silica bead for controlled local hyperthermia,
• Figure 12 represents a graph showing that when the hyperthermic implant obtained in Example 16 is exposed to an alternating magnetic field, the temperature increases, thus demonstrating that the injectable embolizing composition of the present invention loaded with SPIONs is applicable for treatment, for example of a tumor, by hyperthermia.
• the injectable embolizing composition of the present invention may be used for forming in-situ a semi-solid implant for treating urinary incontinence through local tissue augmentation.
• urethral bulking is recognized as a standard treatment.
• the injectable embolizing composition of the present invention provides an efficient alternative.
• the present invention also concerns a coating composition for forming a coating on medical device comprising the iodo-benzylether-PVA of the present invention and a solvent solubilizing the iodo-benzylether-PVA, wherein the concentration of the iodo-benzylether-PVA in the composition is selected in the range from 5 - 65 % so that the composition is capable of forming a radiopaque coating after application on a medical device and solvent evaporation.
• the coating composition of the present invention can be used to deposit a radiopaque coating onto medical devices to make them visible under x-ray imaging.
• Fabrication of the coating can be obtained by deposition of the coating composition of the present invention followed by drying.
• the thickness of the coating will depend on several factors, among them the viscosity of the coating composition.
• the solvents which may be used for solubilizing the iodo-benzylether-PVA comprise tetrahydrofuran, dimethylformamide, dichloromethane, N-methylpyrrolidone, dimethyl sulfoxide.
• said coating composition may be useful for coating the tip of a catheter, as reported in Example 17 and illustrated in Figure 14.
• the present invention further concerns particles, such as nanoparticles and microparticles made of the iodo-benzylether-PVA of the present invention.
• Nanoparticle or microparticles can be produced to help or improve the use of x-ray imaging techniques in the medical field.
• radiopaque particles of the present invention may be used as contrast agent to tag a specific tissue or to follow, upon injection, the flow of a physiological fluid.
• the radiopaque particles of the present invention further contain drugs or pharmaceuticals.
• Radiopaque particles loaded with drugs or biopharmaceuticals can be tracked into the body after their administration, for example after intratumoral injection.
• Radiopaque particles of the present invention can be produced from the iodo- benzylether-PVA of the present invention using any technique known to those skilled in the art of particle manufacturing.
• the following examples are intended to illustrate the present invention. However, they cannot be considered in any case as limiting the scope of the present invention.
• the reactions can be monitored by thin layer chromatography (TLC) on silica with 1/3 ethyl acetate/hexane mixture as mobile phase and observation under UV, illumination at 254 nm wavelength.
• TLC thin layer chromatography
• 1 H and 3 C NMR spectra were recorded on a Brucker 300MHz and Brucker
• iodine contents were calculated based on the degree of substitution, as explained in the description and confirmed by elemental analysis. Radiopacities of iodo-benzylether-PVA were evaluated under X-ray visualization of powdered samples and solutions.
• Pellets were prepared by pressing 1 mg of compound and 100 mg KBr powders.
• PVA 13kDa is a polyvinyl alcohol) having a weight-average molar mass (Mw) of 13 ⁇ 00-23 ⁇ 00 Daltons and a degree of hydrolysis of 87 - 89 % et was purchased from Sigma-Aldrich® Co..
• PVA 47kDa is Mowiol® 6-98, a polyvinyl alcohol) having a weight-average molar mass (Mw) of 47 ⁇ 00 Daltons, a degree of hydrolysis of 98.0-98.8 %, and a viscosity of 6 mPa.s at 4 % in H 2 0, 20°C and was purchased from Sigma-Aldrich® Co..
• PVA 61 kDa is Mowiol® 10-98, a polyvinyl alcohol) having a weight-average molar mass (Mw) of 61 ⁇ 00 Daltons, a degree of hydrolysis of 98.0-98.8 %, and a viscosity of 10 mPa.s at 4 % in H2O, 20°C and was purchased from Sigma- Aldrich® Co..
• PVA 125kDa is Mowioi® 20-98, a poly(viny! alcohol) having a weight-average molar mass (M) of 12'500 Daltons, a degree of hydrolysis of 98.0-98.8 %, and a viscosity of 20 mPa.s at 4 % in H 2 0, 20°C and was purchased from Sigma- Aldrich® Co..
• 2,3,5-triiodobenzoic acid was purchased from Changzhou Dahua Imp. And Exp. Corp. Ltd. (China).
• THF and CH 2 Cl 2 were dried by passing them on a basic activated alumina, AI2O 3 .
• the grafting reaction was adapted from the work reported in "Elaboration of radiopaque iodinated nanoparticles for in situ control of local drug delivery" D. Mawad, H. Mouaziz, A. Penciu, H. Me ier, B. Fenet, H. Fessi, Y. Chevalier;
• the PVA 13kDa was dissolved in dry NMP under nitrogen gas flow and a solution of triiodobenzoyl chloride in NMP was added. Then dry pyridine and DMAP were added. After 12 hours, cold water was added, a paste material precipitated, was filtered and washed with methanol. For the purification step, the crude paste material was dissolved in NMP (concentration: 22 wt%) and cold ethanol was added. A paste material precipitated, was filtered and analyzed by NMR spectrum. The 1 H NMR spectrum showed the grafted PVA free of residual reagent, and traces of solvents.
• the grafted PVA was dissolved in THF (concentration: 30 wt%) and cold water was added. A paste material precipitated, was filtered, washed with methanol and dried under vacuum. The grafted PVA was obtained as a brown solid.
• the reaction conditions were the same as used for the 2,3,5-tri-iodobenzoate-PVA 13kDa in Preparation Example 5.
• the PVA was dissolved in NMP and a solution of 4-mono-iodobenzoyl chloride was added. Then dry pyridine and DMAP were added. After 6 hours, cold water was added and a paste material has precipitated, was filtered and washed with methanol.
• the crude paste material was dissolved in NMP (concentration: 14 wt%) (the mixture is yellow but opaque and all of the particles are dissolved) and 100 ml_ of a solution of NaHC0 3 was added. A solid has precipitated, was filtered and washed with methanol.
• the purity of grafted PVA was 97%.
• the paste material was dissolved in NMP (concentration: 17 wt %) and same volume of cold water was added.
• the solid precipitate was filtrated, washed with methanol to obtain the grafted PVA in the form of a beige solid with a purity of 100 %, as analyzed by NMR with a overall yield of 19 %.
• the grafted PVA was dissolved in THF (concentration: 13 wi %) and cold water was added.
• the grafted PVA (TIB-PVA 13kDa) has precipitated and was analyzed by 1 H-NMR.
• the 1 H-NMR spectrum is represented in Fig. 1 and shows traces of THF in the grafted PVA.
• the purity of grafted PVA was 95 %.
• the paste material was dissolved in THF (concentration: 28 wt%) and two volumes of cold methanol was added. A paste material has appeared, was filtrated, and washed with methanol. The purity was 98%.
• the grafted PVA was dissolved in THF (concentration: 29 wt %) and three volumes of cold water was added. A paste material has appeared, was filtrated, and washed with methanol.
• the grafted PVA (MIB-PVA 13 kDa) was obtained in the form a an orange solid in an overall yield of 24 %.
• the 1 H NMR spectrum of the MIB-PVA 13kDa is represented in Fig. 2.
• the degree of substitution was measured from the areas under the peaks of the NMR spectrum calculated from the integration of the NMR lines.
• the expected iodine content as calculated from the DS was 43 %, and the iodine content confirmed by elemental analysis was 43 %.
• Example 2 The TIB-PVA 13 kDa obtained in Example 1 was dissolved in NMP at the TIB-PVA 13 kDa obtained in Example 1 was dissolved in NMP at the TIB-PVA 13 kDa obtained in Example 1 was dissolved in NMP at the TIB-PVA 13 kDa obtained in Example 1 was dissolved in NMP at the TIB-PVA 13 kDa obtained in Example 1 was dissolved in NMP at
• the injectable composition containing 33 % of TIB-PVA 13kDa dissolved in NMP precipitates as a cohesive mass, and therefore is appropriate as injectable embolizing composition of the present invention.
• the MIB-PVA 13kDa obtained in Example 2 was dissolved in DMSO at a concentration of 33 % w/w and this injectable composition was precipitated in water using a syringe of 1 ml with a needle of 0.9 mm.
• the injectable composition containing 33 % w/w of
• MIB-PVA dissolved in DMSO precipitates as a cohesive mass, and therefore is appropriate as injectable embolizing composition of the present invention.
• compositions containing TIB-PVA 13kDa dissolved in NMP or MIB-PVA 13kDa dissolved in DMSO precipitate as a cohesive mass for concentrations higher than 20 % (w/w).
• Example 2 The TIB-PVA 13kDa obtained in Example 1 was dissolved in NMP at
• Viscosities were measured at a temperature of 25°C using a cone-plate rheometer (Bohlin CV0120 from Malvern Instruments).
• Fig. 5 shows the increase of the viscosity when the concentration of the iodo-benzylether-PVA obtained from PVA 13kDa in the specified solvent increases.
• Fig 5 shows that the viscosity of the embolizing compositions can be tailored by iodo-benzylether-PVA concentration, iodo-benzylether-PVA type, and solvent nature to obtain the high viscosity (ca 500 mPa.s) required for aneurysm embolization as well as the lower viscosity (ca 50 mPa.s) adequate for
• OnyxTM 34 commercial embolizing composition has a viscosity of 55 mPa.s.
• the radiopacity of the composition containing 33 % w/w of TIB- PVA 13kDa of Example 1 in NMP is comparable to that of commercial liquid embolizing compositions (OnyxTM 34 and OnyxTM 18) containing 20 % of
• the embolizing composition containing 33 % w/w of MIB-PVA 13kDa of Example 2 in NMP shows lower radiopacity, as expected from its lower iodine content.
• Embolization of a model aneurysm Two injectable embolizing compositions of the present invention and OnyxTM 34 commercial composition were tested for their ability to fill an aneurysm model.
• We used as a model a 10 mm-diameter sphere affixed to a glass tube.
• the model was flushed with saline using a rotary pump under a 30 cm/s flow speed mimicking blood flow.
• the injectable embolizing composition was injected into the aneurysm model with a 22G needle.
• Fig. 7a shows embolization of an aneurysm model with an injectable embolizing composition (A) of the present invention containing 33 % w/w of TIB-PVA 3kDa obtained in Example 1 in NMP.
• Fig. 7b shows embolization of a aneurysm model with an injectable embolizing composition (B) of the present invention containing 33 % w/w of MIB-PVA 13kDa obtained in Example 2 in NMP.
• Fig. 7c shows embolization of an aneurysm model with OnyxTM 34 commercial embolizing composition.
• FIGs. 7a, 7b and 7c clearly illustrate the ability of the intrinsically radiopaque injectable embolizing compositions (A, B) to fill completely the sphere with a compact mass, in a manner comparable to the commercially available injectable embolizing composition OnyxTM 34. (C).
• Example 7 The same synthesis method as in Example 7 was used in order to graft the 2,3,5- triiodobenzyl bromide with the PVA 47kDa. After conventional steps of purification, TIB-PVA 47kDa including residual NMP was obtained.
• the DS calculated from the NMR lines according to the method of Example 1 was 58 %.
• Example 7 The same synthesis method as in Example 7 was used in order to graft the 2,3,5- triiodobenzyl bromide with the PVA 61 kDa PVA. After conventional steps of purification, TIB-PVA 61 kDa including residual NMP was obtained.
• the DS calculated from the NMR lines according to the method of Example 1 was 46%.
• the DS calculated from the NMR lines according to the method of Example 2 was 51%.
• Anhydrous NMP (280 mL) was transferred from a sealed bottle to the reaction flask using a canula. The mixture was stirred for 30 minutes at 30°C in order to dissolve all of the polymer. The mixture was subsequently cooled and stirred at 50°C. NaOH (2 eq., 160 mmol, 6.4 g), which was freshly ground from pellets into a fine powder, was added in one go. The mixture was stirred at 50°C for 30 minutes, resulting in a colour change of the solution from yellow to brown.
• the mixture was then filtered over a P1-glassfilter, the white crude material was washed with another 500 mL demi-water and subsequently twice with 500 mL acetone.
• the crude product was dried over night under vacuum, and redissolved in THF (200 mL).
• the polymer was then purified via precipitation using toluene as non-solvent. Transferring the THF-solution dropwise to a well-stirred volume of toluene (2 L) yielded white milky mixture, which was filtered over a P4- giassfilter.
• the white solid material was then washed with 500 mL acetone and dried over night under vacuum ( ⁇ 10 "2 mbar) at 100°C, providing 11.5 g of the product as a light-brown solid material.
• the DS is calculated from the 1 H-NMR spectrum recorded in DMSO-d6 containing a small quantity of water represented in Figure 8.
• the following broad signals with chemical shifts of the maxima of the signals are identified :
• the % I is given by
• n 2 number of Iodine atoms on aromatic ring of iodobenzyl unit #2
• the DS calculated from the NMR lines of MTIB-47kDa PVA was 60 %.
• the % I calculated from the DS of MTIB-47kDa PVA was 62 %.
• Embolization formulations of the present invention based on solution of 4-mono- iodobenzyl-PVA (MIB) and 2,3,5-tri-iodobenzyl-PVA (TIB) were synthesized from PVA of various molar masses (13 ⁇ 00-23 ⁇ 00, 47 ⁇ 00, 61 ⁇ 00 and 125 ⁇ 00 g/mol abbreviated 13kDa PVA, 47kDa PVA, 61 kDa PVA and 125kDa PVA).
• MIB 4-mono- iodobenzyl-PVA
• TIB 2,3,5-tri-iodobenzyl-PVA
• the solutions were made by dissolving each of the polymers in NMP at 33 % w/w final concentration (otherwise mentioned).
• mixtures of MIB-PVA 47kDa and TIB-PVA 47kDa in various ratio (MIB -PVA :TIB-PVA 25:75, 40:60, 50:50, 60:40, 75:25 in weight %) were also evaluated.
• Degrees of substitution (DS) of the iodo-benzylether-PVA of the present invention used in this Example were 53 % for MIB-PVA 47kDa, 58 % for TIB-PVA 47kDa, 67 % for MIB-PVA 61 kDa, 58 % for the TIB-PVA 61 kDa and 61 % for the TIB-PVA 125kDa.
• Figures 9a and 9b show the typical plugs obtained with the formulation of the present invention containing TIB-PVA 47kDa at concentrations of 30% and 35% in NMP.
• the highest polymer concentration did show slightly better embolization ability in this specific setting, as well as an increased radiopacity.
• the catheters could generally be withdrawn easily, the IB-PVA and TIB-PVA of the present invention demonstrating little adhesion to the catheters.
• the TIB-PVA 47kDa, TIB-PVA61kDa and TIB-PVA 125kDa could embolize the hydrogel capillary model in a similar manner, although the low molar mass polymer, which demonstrates the lower solution viscosity, may be preferred for the embolization of small vascular structures.
• MIB-PVA 47kDa and MIB-PVA 61kDa could similarly embolize the hydrogel capillary, although showing a slower precipitation than the TIB-PVA.
• a TIB-PVA 47kDa was obtained from Example 13 using equal molar ratio of 4- mono-iodobenzyl bromide and 2,3,5-triiodobenzyl bromide for the synthesis, corresponding to a MIB:TIB 38:62 wt % ratio.
• a liquid embolic formulation was made by dissolving the MTIB-PVA 47kDa in NMP at 33 % w/w final concentration. Heating at 90 °C was used to accelerate dissolution. The liquid formulations were tested in a hydrogel model made of polyvinyl alcohol as show in the previous Example 14.
• MIB-PVA 47kDa having a DS of 56 % was dissolved at 33% w/w in NMP.
• the paste was precipitated into small cylinders, 6 mm diameter.
• This implant was inserted into an adiabatic calorimeter at room temperature and submitted to an alternating magnetic field of 9 mT, 141 kHz (Huttinger TIG-2.5/300) during five minutes.
• the fast increase with a slope of 16 °C/min corresponds to a power dissipation of 5.1 W/g of iron oxide. Such a temperature increase is expected to lead in vivo to thermoablation of surrounding tissues.
• Doxorubicine hydrochloride was dissolved in N-methyl pyrrolidone (NMP, at 25 mg/mL).
• NMP N-methyl pyrrolidone
• TIB-PVA 47kDa having a DS of 58 % was added at 33 % w/w final concentration.
• the solution was injected into cylindrical alginate molds to produce 6-mm diameter plugs (ca 0.3 g each).
• the doxorubicine-loaded samples were incubated in 00 ml_ saline at 37 °C under agitation.
• Doxorubicine was quantified by measurements of the optical absorption of the supernatant at 479 nm wavelength.
• Figure 13 shows the obtained gradual release of the anticancer agents over 3 days.
• a radiopaque coating was deposited onto a catheter tip by dipping and solvent evaporation. Briefly, TBI-PVA 47kDa having a DS of 58 % were dissolved in NMP at 40°C at a final concentration of 33 % w/w. The tip of a catheter (Cordis Envoy GC) was dipped for 5 s into the radiopaque polymer solution, withdrawn and dried at room temperature, keeping the catheter under axial rotation to obtain an even coating. The tip coated with TIB-PVA 47kDa is illustrated in Figs. 14a and 14b. Radiopaque and catheter polymers were bound together by virtue of solvent evaporation. Other solvents were assessed, such as DMSO, leading to similar radiopaque coatings.
• Radiopaque nanoparticles were prepared by the nanoprecipitation method as follows: 100 mg of MIB-PVA 47kDa having a DS of 49% was dissolved in THF (20 ml) at room temperature to form the diffusing phase. The diffusing phase was then added by means of a syringe to the dispersing phase constituted of phosphate buffered saline (PBS, 40 ml) containing 0.25% surfactant Pluronic F68 under stirring. The aqueous phase turned milky as the organic phase was poured, leading to a homogeneous milky dispersion at the end. THF was evaporated under reduced pressure. The mean diameter of the nanoparticles, as measured using a Malvern NanoZS instrument, was 170 nm, with a monomodal distribution.
• the nanoparticles suspensions were incubated at 37 °C in phosphate-buffered saline (PBS). At given time points, the nanoparticles were collected by centrifugation and the supernatants of centrifuged suspensions were analyzed by UV absorbance at 250 nm wavelength - the absorbance maxima of 4-monoiodobenzoic acid.
• Figure 15 displays the time- evolution of the absorbance, reflecting the release of degradation products.

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